LENG8 granule regulates alternative polyadenylation in mammals

Membraneless organelles participate in multiple cellular processes and layers of gene regulation. Alternative polyadenylation (APA) is emerging as a widespread mechanism for controlling gene expression by generating distinct 3′ untranslated regions (UTRs) in transcripts. However, whether specific membraneless organelles exist in mammals to regulate APA remains largely unknown. Here, we unveil a previously unidentified nuclear body, termed LENG8 granule, which functions as an active hub for APA regulation. LENG8 deletion leads to extensive 3′UTR lengthening in both cultured cells and male germ cells. LENG8 granules recruit cleavage and polyadenylation (CPA) factors and promote their local assembly, thereby favoring the utilization of proximal poly(A) sites (pPASs). Additionally, LENG8 granules function both independently and cooperatively with nuclear speckles to regulate mRNA 3' end processing. We also elucidate the pivotal roles of YTHDC1-m6A landscapes in LENG8 granule formation/maintenance and target selection. The 3′UTR length of targets correlates with the formation and properties of LENG8 granules in a cell type-specific and developmental stage-dependent manner. Our findings highlight LENG8 as a key factor in 3′ end processing and uncover a hitherto unrecognized nuclear body involved in mammalian APA regulation, which broadens our understanding of membraneless organelles and their role in poly(A) site selection.